rs1057518646

Positions:

• chr12-7088720-GGCACTTGATGA-GTGTCC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001733.7(C1R):​c.917_927delTCATCAAGTGCinsGGACA​(p.Ile306_Cys309delinsArgThr) variant causes a missense, disruptive inframe deletion, splice region change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense, disruptive_inframe_deletion, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.42

Genes affected

C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

C1R (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001733.7.
• PP5: Variant 12-7088721-GCACTTGATGA-TGTCC is Pathogenic according to our data. Variant chr12-7088721-GCACTTGATGA-TGTCC is described in ClinVar as [Pathogenic]. Clinvar id is 267355.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C1R	NM_001733.7	c.917_927delTCATCAAGTGCinsGGACA	p.Ile306_Cys309delinsArgThr	missense_variant, disruptive_inframe_deletion, splice_region_variant		ENST00000647956.2	NP_001724.4
C1R	NM_001354346.2	c.959_969delTCATCAAGTGCinsGGACA	p.Ile320_Cys323delinsArgThr	missense_variant, disruptive_inframe_deletion, splice_region_variant			NP_001341275.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C1R	ENST00000647956.2	c.917_927delTCATCAAGTGCinsGGACA	p.Ile306_Cys309delinsArgThr	missense_variant, disruptive_inframe_deletion, splice_region_variant			NM_001733.7	ENSP00000497341.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, periodontal type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 31, 2016	- -
Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, Medical University Innsbruck	Aug 23, 2016	- -

Ehlers-Danlos syndrome, periodontal type 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Oct 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518646; hg19: chr12-7241317;